Project Summary/Abstract: The invention of new methods to access chiral organic molecules is a critical objective in modern organic chemistry as it is essential for the efficient synthesis of pharmaceutical agents. This is especially relevant as the pharmaceutical industry is making efforts to increase the 3D complexity of drug candidates. Despite substantial progress in the field of stereoselective chemical synthesis, many structures remain challenging to prepare in useful quantities. Therefore, development of new methods and strategies for the chemical synthesis of stereochemically and topologically complex molecules is of contemporary interest. The long-term goals of our research program are to introduce general and efficient strategies for the stereoselective synthesis of difficult-to-access molecular frameworks found in important bioactive molecules. Towards this end, we are interested in the conversion of abundant and readily available alkenes to more complex structures through difunctionalization reactions. This approach is attractive because the rapid buildup of complexity can be achieved as two new bonds and two new stereocenters are generated in a single operation. The studies described in this application focus on two distinct programs. The first is the development of stereoselective cross-coupling reactions of Csp3-nucleophiles that are catalytically generated in situ from simple alkenes. Our rationale for development of these reactions is that widely available alkenes, diboron reagents, and organohalides are converted to synthetically versatile intermediates. Based on our earlier work, we are developing Pd/Cu-cooperative catalytic systems for the arylboration of activated alkenes and in particular demonstrating the functionalization of nitrogen containing heterocycles. In addition, we are developing a general strategy for unactivated alkene difunctionalization with Ni-catalysis. In the second program of research, we are developing methods for the enantioselective synthesis of cyclobutanes by [2+2] cycloaddition of alkenes and electron deficient allenes. Our rationale for the development of these reactions is that due to the concerted asynchronous nature of these processes, a broad range of alkenes can be utilized. This allows for the synthesis of a diverse range of stereochemically complex cyclobutanes. The rings generated by these transformations are directly found in bioactive molecules, can be subjected to a variety of reactions, and represent novel building blocks for drug discovery. Overall, these studies in reaction development will introduce new concepts and strategies as well as provide access to new building blocks for chemical synthesis by exploring new cross-coupling paradigms and cycloaddition reactions.